Pharmaceutical formulation

ABSTRACT

A pharmaceutical formulation comprising an amoxycillin hydrate and an effervescent couple, for example citric acid plus sodium bicarbonate or sodium glycine carbonate, or tartaric acid or malic acid plus sodium carbonate. Potassium equivalents of these sodium salts may be used. The formulations may be free flowing powders or granules, or tablets.

This is a continuation of application Ser. No. 07/934,757, filed Oct. 7,1992 now abandoned.

The present invention relates to pharmaceutical compositions for oraladministration in the treatment of bacterial infections.

In some clinical situations, to improve patient compliance, it isdesirable to administer medicaments orally in liquid form as suspensionsor solutions.

EP-A-0080862 (Beecham) discloses water-dispersible compositions ofamoxycillin trihydrate, in which the amoxycillin trihydrate and otheringredients are formulated with a non-hygroscopic water-soluble binder.

Solutions are favoured over suspensions for oral administration, sincedrugs in solution are more rapidly absorbed. Solutions are also oftenmore acceptable to patients, in terms of patatability. It has beenproposed to prepare dry effervescent formulations of medicaments inwhich, on addition to water, a medicament is dispersed in the water bythe effervescing action and dissolves either as a result of theagitation or by interaction with components of the formulation. Forexample, GB-A-1287475 (Aspro-Nicholas) describes an effervescentformulation of aspirin. In order to obtain effective contact of theaspirin with the solubilising compounds during effervescence, theaspirin particles are pre-coated with a special readily wettablecoating.

Effervescent formulations of antibiotics are disclosed in GB-A-1300998(Biochemie). In this disclosure it is considered essential that theantibiotic is in the form of a water-soluble salt in the dryformulation. For amoxycillin this would be disadvantageous because thewater-soluble sodium salt is very hygroscopic and unstable when it hasabsorbed water.

A dispersible tablet formulation containing amoxycillin is disclosed inEP-0281200-A1 (Gist-Brocades). This formulation does not result in aclear solution of dissolved amoxycillin, but a suspension.

We have now discovered that amoxycillin that is not in salt form can beprovided as an effervescent formulation in which it is solubilised oncontact with water, and in particular that will produce a clear solutionfor oral administration.

According to the present invention there is provided a pharmaceuticalformulation comprising an amoxycillin hydrate and an effervescent couplewhich comprises an acid component and an alkaline component, whichgenerates carbon dioxide on contact with water, in which the alkalinecomponent of the couple is present in excess of the stoichiometricequivalent of the acid component.

The amoxycillin hydrate is preferably amoxycillin trihydrate and may beprovided in conjunction with a β-lactamase inhibitor, such as clavulanicacid or a salt thereof preferably potassium clavulanate. A suitableratio range of amoxycillin: clavulanic acid or clavulanate saltequivalent is 12:1 to 1:1, preferably 7:1 to 1:1, 4:1 to 1:1 or 2:1 to1:1, by weight. A suitable proportion of amoxycillin in the formulationis 10-30% by weight, e.g. 10-25%.

The effervescent couple is preferably based on citric acid and sodiumbicarbonate or sodium glycine carbonate, but other solid acid/carbonatecouples may be used, for example tartaric or malic acid and sodiumcarbonate or potassium bicarbonate or mixtures of these acid andalkaline components. The effervescent couple is provided in a sufficientamount to rapidly disperse and assist dissolution of the components ofthe formulation. The corresponding potassium salts of the alkalinecomponent may be used together with the sodium salts (or as asubstitute) to avoid excessive levels of sodium ions. This may benecessary when high doses of amoxycillin are included in thecomposition.

The alkaline component should be present in sufficient amount to bothneutralize the acid component and to solubilise the amoxycillin byformation of soluble e.g. sodium/potassium, salts. The aim is that theresulting aqueous solution should have a pH of not less than 8 toachieve solubilization of amoxycillin trihydrate. Typically thecomposition may contain 50-75% of an alkaline component such as sodiumor potassium hydrogen carbonate or glycine carbonate, by weight. Asuitable mixed alkaline component is a 3-1.5:1, for example 2.5-2:1 byweight mixture of sodium glycine carbonate: potassium bicarbonate.

Typically the composition may contain 2-25%, e.g. 5-20%, e.g. 5-17.5%,by weight of an acid component such as citric acid.

The amounts of effervescent couple and excess alkaline componentrequired to achieve rapid and complete solubilisation of a particularamoxycillin dosage can be determined by simple experiments. For doses ofamoxycillin of 1 g or more, suitable ranges of molar ratios of sodiumglycine carbonate: amoxycillin: potassium bicarbonate: citric acid inthe formulation are 4-10: 1-3: 5-10: 1, for example 5-8: 1.5-2.5:6.5-7.5: 1. Citric acid is tribasic, and suitable molar ratios of otheracids may be calculated accordingly. The suitable molar ratio expressedabove corresponds to a weight ratio sodium glycine carbonate 4.8-12:amoxycillin 1.9-5.7: potassium bicarbonate 2-6-5.1: citric acid 1, witha preferred weight ratio of sodium glycine carbonate: amoxycillin of atleast 1.66.

Suitable ranges of molar ratios of sodium glycine carbonate:amoxycillin: citric acid are 1.5-4.5: 0.2-1: 1. The suitable molar ratioexpressed above corresponds to a weight ratio sodium glycine carboante:amoxycillin: citric acid of 1.7-5.5: 0.4-1.9: 1.

For lower doses of amoxycillin, for example 500 mg, 250 mg and 125 mgthe levels of sodium ions is not excessive and the inclusion ofpotassium bicarbonate is not necessary.

Conventional excipients, such as colourings, fillers, diluents,sweeteners and flavourings may be added to the formulations, typicallyin an amount up to around 10% by weight, e.g. 1-7.5%. A suitablesweetener is aspartame.

The formulations are typically in the form of free flowing powders orgranules, or tablets.

Soluble tablets may contain conventional water-soluble lubricants suchas sodium lauryl sulphate or sodium benzoate, typically up to around7.5% or less. Alternatively tablets may be made using externallubrication on liquid-lubricated presses, or on double-sided presseswhere solid lubricant placebo compacts containing, for example,magnesium stearate are made on one side, continuously pre-lubricatingthe dies. The manufacturing method may be entirely conventional, e.g.formation of a granulate intermediate containing some or all of themilled components, followed by optionally blending with the othercomponents and then pressing into tablets.

Soluble tablets are preferably conventionally packaged in protectivecontainers such as screw cap bottles, aluminium foil sachets, plasticsor metal tubes, or aluminium blister packs. Soluble powders or granulesare preferably conventionally packaged in individual aluminium foilsachets, each containing a unit dose of the antibiotic. It may beappropriate to incorporate a desiccant in the packaging.

The amount of amoxycillin in a unit dose will depend on the infection tobe treated and the assay of the amoxycillin. The unit-dose will berepeated according to the usual regime for amoxycillin treatments.Typically a unit dose may contain 3000, 875 or 125 mg of amoxycillin pertablet or sachet, or an intermediate dose.

The invention also provides a formulation as defined above for use inthe treatment of bacterial infections in humans or animals.

The invention also provides a method of treatment of bacterialinfections in humans or animals which comprises administering to thehuman or animal patient a formulation as defined above in anantibacterially effective amount.

The invention also provides a process for the preparation of apharmaceutical formulation which comprises admixing an amoxycillinhydrate and an effervescent couple, the couple comprising an acidcomponent and an alkaline component which generates carbon dioxide oncontact with water, the alkaline component of the couple being presentin excess of the stoichiometric equivalent of the acid component.

The invention also provides a use, of an admixture of an amoxycillinhydrate and an effervescent couple, the couple comprising an acidcomponent and an alkaline component which generates carbon dioxide oncontact with water, the alkaline component of the couple being presentin excess of the stoichometric equivalent of the acid component, in themanufacture of a medicament for the treatment of bacterial infections.

The invention is illustrated by the following Examples.

EXAMPLE 1

    ______________________________________                                        3 g Dose Soluble Sachet                                                       Ingredients        g/dose  % w/w                                              ______________________________________                                        Amoxycillin trihydrate                                                                           3.000   22.5                                               (as free acid)                                                                Potassium bicarbonate                                                                            2.800   21.04                                              Sodium glycine carbonate                                                                         6.212   46.7                                               Citric acid        0.800   6.01                                               Aspartame          0.150   1.13                                               Sodium saccharin   0.040   0.30                                               Lemon juice flavour                                                                              0.220   1.65                                               Cinnamon flavour   0.085   0.64                                               ______________________________________                                    

Reconstitution: Add the contents of each sachet to 200 mls of water andstir gently.

Manufacturing Process

The amoxycillin trihydrate was passed through an Apex 114 mill fittedwith a 0.027 inch (0.686 mm) aperture screen using hammers forward at4590 rpm.

The potassium bicarbonate, sodium glycine carbonate, aspartame, driedsaccharin sodium and citric acid were passed through a 30 mesh screenand placed in a blender with the milled amoxycillin trihydrate. The mixwas blended for 20 minutes at slow speed. The blend was then passedthrough a roller compactor, and the compact passed through an Apex 114mill fitted with a 0.063 inch (1.6 mm) aperture screen, using knivesforward at 2880 rpm, into a blender.

The flavours were screened through a 20 mesh screen into the blender,and the mix blended for 15 minutes at slow speed. The final mixture wasfilled into sachets at a weight calculated to deliver the required doseof amoxycillin.

EXAMPLE 2

    ______________________________________                                        1 g Dose Soluble Sachets                                                      Ingredients         mg/sachet                                                                              (% w/w)                                          ______________________________________                                        Amoxycillin Trihydrate                                                                            875.0    19.06                                            equivalent to Amoxycillin free acid                                           Potassium Clavulanate                                                                             125.0     2.72                                            equivalent to Clavulanic acid                                                 Potassium bicarbonate                                                                             930.0    20.26                                            Citric acid (anhydrous)                                                                           270.0     5.88                                            Aspartame            40.0     0.87                                            Sodium saccharin     10.4     0.23                                            Lemon dry flavour    73.0     1.59                                            Cinnamon flavour     28.0     0.61                                            Sodium glycine carbonate                                                                          2238.6   48.77                                            ______________________________________                                    

Manufacturing Process

The amoxycillin trihydrate was passed through an Apex 114 mill fittedwith a 0.027 inch (0.686 mm) screen using hammers forward at 4,600 rpm.All other ingredients were passed though a 30 mesh screen. The reducedamoxycillin trihydrate and other ingredients were blended in a suitablysized Y-cone blender for 20 minutes. The resultant mixture was compactedon a roller compactor, and the compact was reduced to granules andclassified.

EXAMPLE 3

    ______________________________________                                        3.25 g Dose Soluble Sachet                                                    Ingredients       mg/dose   % (w/w)                                           ______________________________________                                        Amoxycillin trihydrate                                                                          3000      25.0                                                                (as free acid)                                              Potassium clavulanate                                                                            250       2.08                                                               (as free acid)                                              Sodium glycine carbonate                                                                        4968      41.39                                             Potassium bicarbonate                                                                           2504      20.86                                             Citric acid anhydrous                                                                            640       5.33                                             Aspartame          150       1.25                                             Sodium saccharin   40        0.33                                             Golden syrup flavour                                                                             150       1.25                                             Banana flavour     300      2.5                                               ______________________________________                                    

EXAMPLE 4

    ______________________________________                                        156.3 mg Dose Soluble Tablet                                                  Ingredients       mg/tablet % (w/w)                                           ______________________________________                                        Amoxycillin trihydrate                                                                          125.00    10.43                                                               (as free acid)                                              Potassium clavulanate                                                                           31.25      2.61                                                               (as free acid)                                              Sodium glycine carbonate                                                                        625.00    52                                                Citric acid anhydrous                                                                           200.00    16.69                                             Sodium benzoate   66.90      5.58                                             Aspartame         37.50      3.13                                             Golden syrup flavour                                                                            37.50      3.13                                             Banana flavour    75.00      6.26                                             ______________________________________                                    

This tablet is compressed on 9/16 inch (14.288 mm) bevel-flat punches.

EXAMPLE 5

    ______________________________________                                        125 mg Dose Soluble Tablets                                                   Ingredients       mg/tablets                                                                              % (w/w)                                           ______________________________________                                        Amoxycillin trihydrate                                                                          125.0     18.89                                                               (as free acid)                                              Sodium glycine carbonate                                                                        406.3     61.39                                             Citric acid anhydrous                                                                           93.8      14.17                                             Aspartame         12.1       1.83                                             Lemon juice flavour                                                                             17.8       2.69                                             Cinnamon flavour   6.8       1.03                                             ______________________________________                                    

Manufacturing Process

The amoxycillin trihydrate was passed through an Apex 114 mill fittedwith a 0.027 inch (0.686 mm) screen, hammers forward, at 7200 rpm into ablender. The citric acid was passed through an Apex 114 mill fitted witha 0.040 inch (1 mm) screen, hammers forward, at 7200 rpm into theblender. The other ingredients except for the flavours were passedthough a 30 mesh screen into the blender. The mix was blended for 20minutes, and the blend slugged on one side of a Manesty BB4 double-sidedpress fitted with 1/2 inch (12.5 mm) round bevelled flat tooling. Alubricating mix consisting of 3% magnesium stearate in lactose wascompressed on the other side of the machine. The slugs were milled on anApex 114 mill fitted with a 0.063 (1.6 mm) inch screen, knives forwardat 2900 rpm. The flavours were passed through a 30 mesh screen andblended with the reduced slugs for 20 minutes. The blend was compressedon the double-sided press fitted with the same tooling as used toprepare the slugs, and lubricated in the same manner.

EXAMPLE 6 250 mg Dose Soluble Tablets

250 mg tablets were prepared by exactly doubling the quantitiesdescribed in Example 5, and using an identical process except forreplacing the 1/2 inch (12.5 mm) punches by 5/8 inch (15.875 mm)punches.

In the formulations of examples 1-6 above the relative roportions ofcomponents are preferably maintained within ±10% of the statedquantities.

We claim:
 1. A pharmaceutical formulation having a composition within±10% consisting of:

    ______________________________________                                        Ingredient               % w/w                                                ______________________________________                                        Amoxycillin trihydrate                                                                           as free acid                                                                            22.5                                             Potassium bicarbonate        21.04                                            Sodium glycine carbonate     46.7                                             Citric acid                  6.01                                             Aspartame                    1.13                                             Sodium saccharin             0.30                                             Lemon juice flavour          1.65                                             Cinnamon flavour             0.64.                                            ______________________________________                                    


2. A pharmaceutical formulation having a composition within ±10%consisting of

    ______________________________________                                        Ingredients           % w/w                                                   ______________________________________                                        Amoxycillin Trihydrate equivalent                                                                   19.06                                                   to Amoxycillin free acid                                                      Potassium Clavulanate equivalent                                                                    2.72                                                    to Clavulanic acid                                                            Potassium bicarbonate 20.26                                                   Citric acid (anhydrous)                                                                             5.88                                                    Aspartame             0.87                                                    Sodium saccharin      0.23                                                    Lemon dry flavour     1.59                                                    Cinnamon flavour      0.61                                                    Sodium glycine carbonate                                                                            48.77.                                                  ______________________________________                                    


3. A pharmaceutical formulation having a composition within ±10%consisting of:

    ______________________________________                                        Ingredients              % w/w                                                ______________________________________                                        Amoxycillin trihydrate                                                                           as free acid                                                                            25.0                                             Potassium clavulanate                                                                            as free acid                                                                            2.08                                             Sodium glycine carbonate     41.39                                            Potassium bicarbonate        20.86                                            Citric acid anhydrous        5.33                                             Aspartame                    1.25                                             Sodium saccharin             0.33                                             Golden syrup flavour         1.25                                             Banana flavour               2.5.                                             ______________________________________                                    


4. A pharmaceutical formulation being a tablet formulation having acomposition within ±10% consisting of:

    ______________________________________                                        Ingredients              % w/w                                                ______________________________________                                        Amoxycillin trihydrate                                                                           as free acid                                                                            10.43                                            Potassium clavulanate                                                                            as free acid                                                                            2.61                                             Sodium glycine carbonate     52.00                                            Citric acid anhydrous        16.69                                            Sodium benzoate              5.58                                             Aspartame                    3.13                                             Golden syrup flavour         3.13                                             Banana flavour               6.26.                                            ______________________________________                                    


5. A pharmaceutical formulation being a tablet formulation having acomposition within ±10% consisting of:

    ______________________________________                                        Ingredients              % w/w                                                ______________________________________                                        Amoxycillin trihydrate                                                                           as free acid                                                                            18.89                                            Sodium glycine carbonate     61.39                                            Citric acid anhydrous        14.17                                            Aspartame                    1.83                                             Lemon juice flavour          2.69                                             Cinnamon flavour             1.03.                                            ______________________________________                                    